Abstract Significance: Proliferative vitreoretinopathy (PVR) is a blinding orphan indication that occurs in 5-10% of patients receiving rhegmatogenous retinal reattachment surgery, and accounts for ~75% of all primary surgical failures. PVR is characterized by migration and proliferation of ectopic cells beneath or on the surface of the retina, which then assemble into a membrane, causing retinal traction and detachment. Since currently there is no effective therapeutics that reverse the cell proliferation process, the only treatment option for PVR is additional surgeries, which often have very poor vision outcome due to retinal damage from recurrent detachment, risking blindness. There is an urgent unmet need for novel pharmacotherapies for PVR. Hypothesis and aims: Extensive research established PDGFs as leading candidates for treating PVR. However, inhibiting multiple PDGF targets may be required to be effective. Aptamers are single-stranded oligonucleotides that bind to molecular targets in a similar manner to monoclonal antibodies (mAbs), but possess unique advantages for treating ocular diseases such as PVR, thanks to its small size, superior stability, and lack of immunogenicity. We have already developed a fully modified aptamer for PDGF-B, and verified its potency and stability in vitro and bioactivity in vivo in two different animal models. We propose to develop 100% modified, high potency aptamers against PDGF-A, -B, and -C, to extend the key advantages of aptamers to this potential first-in-class treatment.